Blood brain barrier shuttle

Abstract

The present invention relates to blood brain barrier shuttles that bind receptors on the blood brain barrier (R/BBB) and methods of using the same.

What is claimed is: 
     
         1 . A blood brain barrier shuttle comprising a brain effector entity, a linker and one monovalent binding entity which binds to a blood brain barrier receptor, wherein the linker couples the effector entity to the monovalent binding entity which binds to the blood brain barrier receptor. 
     
     
         2 . The blood brain barrier shuttle of  claim 1 , wherein the monovalent binding entity which binds to the blood brain barrier receptor is selected from the group consisting of proteins, polypeptides and peptides. 
     
     
         3 . The blood brain barrier shuttle of  claim 1 , wherein the monovalent binding entity which binds to the blood brain barrier receptor comprises a molecule selected from the group consisting of a blood brain barrier receptor ligand, scFv, Fv, sFab, VHH, preferably a sFab. 
     
     
         4 . The blood brain barrier shuttle of  claim 1 , wherein the blood brain receptor is selected from the group consisting of transferrin receptor, insulin receptor, insulin-like growth factor receptor, low density lipoprotein receptor-related protein 8, low density lipoprotein receptor-related protein 1 and heparin-binding epidermal growth factor-like growth factor, preferably transferrin receptor. 
     
     
         5 . The blood brain barrier shuttle of  claim 1 , wherein the monovalent binding entity which binds to the blood brain barrier receptor comprises one scFab directed to the transferrin receptor preferably a scFab recognizing an epitope in the transferrin receptor comprised within the amino acid sequence of Seq. Id. No. 14, 15 or 16. 
     
     
         6 . The blood brain barrier shuttle of  claim 1 , wherein the brain effector entity is selected from the group consisting of neurological disorder drugs, neurotrophic factors, growth factors, enzymes, cytotoxic agents, antibodies directed to a brain target, monoclonal antibodies directed to a brain target, and peptides directed to a brain target. 
     
     
         7 . The blood brain barrier shuttle of  claim 6 , wherein the brain target is selected from the group consisting of β-secretase 1, Aβ, epidermal growth factor, epidermal growth factor receptor 2, Tau, phosphorylated Tau, apolipoprotein E4, alpha synuclein, oligomeric fragments of alpha synuclein, CD20, huntingtin, prion protein, leucine rich repeat kinase 2, parkin, presenilin 2, gamma secretase, death receptor 6, amyloid precursor protein, p75 neurotrophin receptor, and caspase 6. 
     
     
         8 . The blood brain barrier shuttle of  claim 1 , wherein the brain effector entity is selected from the group consisting of proteins, polypeptides, and peptides. 
     
     
         9 . The blood brain barrier shuttle of  claim 8 , wherein the monovalent binding entity which binds to the blood brain receptor is coupled to the C-terminal end of the brain effector entity by the linker. 
     
     
         10 . The blood brain barrier shuttle of  claim 1 , wherein the brain effector entity comprises a full length antibody directed to a brain target, preferably a full length IgG. 
     
     
         11 . The blood brain barrier shuttle of  claim 10  comprising the full length IgG antibody as brain effector entity, the linker and one scFab as the monovalent binding entity which binds the blood brain receptor, wherein the scFab is coupled by the linker to the C-terminal end of the Fc part of one of the heavy chains of the IgG antibody. 
     
     
         12 . The blood brain barrier shuttle of  claim 10 , wherein the effector entity is a full length antibody directed to Aβ. 
     
     
         13 . The blood brain barrier shuttle of  claim 12 , wherein the antibody directed to Aβ comprises (a) H-CDR1 comprising the amino acid sequence of Seq. Id. No. 5, (b) H-CDR2 comprising the amino acid sequence of Seq. Id. No. 6, (c) H-CDR3 comprising the amino acid sequence of Seq. Id. No. 7, (d) L-CDR1 comprising the amino acid sequence of Seq. Id. No. 8, (e) L-CDR2 comprising the amino acid sequence of Seq. Id. No. 9 and (f) L-CDR3 comprising the amino acid sequence of Seq. Id. No. 10. 
     
     
         14 . The blood brain barrier shuttle of  claim 13 , wherein the antibody directed to Abeta comprises a V H  domain comprising the amino acid sequence of Seq. Id. No. 11 and a V L  domain comprising the amino acid sequence of Seq. Id. No. 12. 
     
     
         15 . The blood brain barrier shuttle of  claim 10 , wherein the effector entity is a full length antibody directed to phosphorylated Tau and the monovalent binding entity is one scFab directed to the transferrin receptor. 
     
     
         16 . The blood brain barrier shuttle of  claim 10 , wherein the effector entity is a full length antibody directed to alpha synuclein and the monovalent binding entity is one scFab directed to the transferrin receptor. 
     
     
         17 . The blood brain barrier shuttle of  claim 1 , wherein the linker is a peptide linker, preferably a peptide which is an amino acid sequence with a length of at least 20 amino acids, more preferably with a length of 25 to 50 amino acids. 
     
     
         18 . The blood brain barrier shuttle of  claim 1 , wherein the monovalent binding entity which binds to the blood brain barrier receptor comprises a CH2-CH3 Ig entity and one sFab which binds to the blood brain barrier receptor, wherein the sFab is coupled to a C-terminal end of the CH2-CH3 Ig entity by a second linker. 
     
     
         19 . The blood brain barrier shuttle of  claim 18  comprising the brain effector entity, the linker, the CH2-CH3 Ig domain, the second linker and one sFab which binds to the blood brain barrier receptor, wherein the brain effector entity is coupled by the first linker to a N-terminal end of the CH2-CH3 Ig domain and the sFab is coupled to a C-terminal end of the CH2-CH3 Ig domain by the second linker. 
     
     
         20 . The blood brain barrier shuttle of  claim 18 , wherein the CH2-CH3 Ig entity is a CH2-CH3 IgG entity. 
     
     
         21 . An isolated nucleic acid encoding the blood brain barrier shuttle of  claim 1 . 
     
     
         22 . A host cell comprising the nucleic acid of  claim 21 . 
     
     
         23 . A pharmaceutical formulation comprising the blood brain barrier shuttle of  claim 1  and a pharmaceutical carrier. 
     
     
         24 . The blood brain barrier shuttle of  claim 1 , wherein the blood brain barrier shuttle transports the brain effector entity across the blood brain barrier. 
     
     
         25 . A fusion protein for transporting a brain effector entity across the blood brain barrier comprising a CH2-CH3 Ig entity, a linker and one sFab directed to a blood brain barrier receptor, wherein the sFab is coupled to a C-terminal end of the CH2-CH3 Ig entity by the linker. 
     
     
         26 . The fusion protein of  claim 25 , wherein the brain effector entity is selected from the group consisting of neurological disorder drugs, neurotrophic factors, growth factors, enzymes, cytotoxic agents, antibody fragments or peptides directed to a brain target selected from the group consisting of scFv, Fv, scFab, Fab, VHH, F(ab′) 2 . 
     
     
         27 . The fusion protein to transport the brain effector entity across the blood brain barrier of  claim 25 , wherein the sFab directed to the blood brain barrier receptor is a sFab directed to the transferrin receptor, preferably a scFab recognizing an epitope in the transferrin receptor comprised within the amino acid sequence of Seq. Id. No. 14, 15 or 16. 
     
     
         28 . The fusion protein of  claim 25 , wherein the linker is a peptide linker. 
     
     
         29 . The fusion protein of  claim 25 , wherein the CH2-CH3 Ig entity is a CH2-CH3 IgG entity. 
     
     
         30 . An isolated nucleic acid encoding the fusion protein of  claim 25 . 
     
     
         31 . A host cell comprising the nucleic acid of  claim 30 . 
     
     
         32 . A conjugate comprising the fusion protein of  claim 25  and a brain effector entity, wherein the brain effector entity is coupled by a linker to a N-terminal end of the CH2-CH3 Ig entity of the fusion protein. 
     
     
         33 . The conjugate of  claim 32 , wherein the brain effector entity is selected from the group consisting of proteins, polypeptides, and peptides. 
     
     
         34 . The conjugate of  claim 33 , wherein a C-terminal end of the effector entity is coupled to the N-terminal end of the CH2-CH3 Ig entity by the linker. 
     
     
         35 . A pharmaceutical formulation comprising the conjugate of  claim 32  and a pharmaceutical carrier. 
     
     
         36 . A method of treating a subject with a neurodegenerative disorder, the method comprising administering to the subject the blood brain shuttle of  claim 1 . 
     
     
         37 . The method of  claim 36 , wherein the neurodegenerative disorder is Alzheimer's disease. 
     
     
         38 . A method of treating a subject with a neurodegenerative disorder, the method comprising administering to the subject the conjugate of  claim 32 . 
     
     
         39 . The method of  claim 38 , wherein the neurodegenerative disorder is Alzheimer's disease.